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Analyzing Complex Polygenic Traits
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Bernard R. Lauwerys, Edward K. Wakeland
Recently, high-density cDNAs or oligonucleotide spotted microarrays have been successfully introduced in the process of candidate gene identification. The availability of slides containing large arrays (>20,000 probes) and developments in the bioinformatic tools required for useful interpretation of the data, make microarrays a powerful instrument for screening differential gene expression between diseased versus control animals. Rozzo et al recently studied differential gene expression in B6 versus B6.Nba2 spleen cells. Nba2 is a NZB (New Zealand Black) autoimmunity mouse locus that has been associated with lupus traits in BWF1 lupus prone mice. High levels of IgG autoantibodies but no nephritis characterize B6.Nba2, a congenic strain of mice that harbors the Nba2 susceptibility interval in a B6 resistant background. Strikingly, (B6.Nba2 × NZW)F1 hybrids display a high rate of autoantibody production and glomerulonephritis, while (B6 × NZW)F1 mice do not develop any feature of autoimmunity. Using microarrays, the authors found consistent increase in Ifi202 and a reciprocal decrease in Ifi203 (Ifi are a family of interferon-activated genes) gene expression in B6.Nba2 spleen cells. Real-time PCR experiments showed that B cells and non-B, non-T cells were responsible for the increased expression of Ifi202. Interestingly, a SNP in the promoter region of the gene correlated with levels of expression: high in NZB and Balb/c mice that share the 95 C allele, low in NZW, B6 and B10 that are characterized by a 95 T allele.61
Global proteomics of fibroblast cells treated with bacterial cyclic dinucleotides, c-di-GMP and c-di-AMP
Published in Journal of Oral Microbiology, 2022
Kenneth I. Onyedibe, Samira Elmanfi, Uma K. Aryal, Eija Könönen, Ulvi Kahraman Gürsoy, Herman O. Sintim
Accumulating evidences indicate that beyond upregulating the expression of interferons and cytokines via the STING pathway, CDNs also affect other non-STING pathways in a differential manner. For example, Woodward et al. demonstrated that c-di-AMP but not cGAMP binds to the oxidoreductase, RECON to regulate NF-kB [12]. cGAMP has also been shown to regulate ULK1 kinase via AMPK [13]. Using label-free quantitative proteomics, we previously demonstrated that c-di-GMP and 2ʹ3’cGAMP differentially affect pathways in macrophages [14]. As would be expected in macrophages, many of the proteins upregulated by the CDNs were related to cytokine signaling and interferon production including interferon-induced proteins 47, 202 and 204 (IFI47, IFI202, IFI204) and interferon-induced protein with tetratricopeptide repeats 1, 2 or 3 (IFIT1, IFIT2, IFIT3) [14]. Ubiquitin-like protein ISG15 (ISG15) was also significantly upregulated by cyclic dinucleotides [14]. The modulations of other processes by CDNs, other than inflammatory pathways, have not been fully characterized and this work aimed to fill this gap in knowledge, using fibroblast cell as a model.
Double-edged effects of interferons on the regulation of cancer-immunity cycle
Published in OncoImmunology, 2021
Xiao Zhang, Song Wang, Yuanyuan Zhu, Minghui Zhang, Yan Zhao, Zhengbin Yan, Qiuxu Wang, Xiaobo Li
Type I IFNs not only promote the priming of T cells, but also prolong the survival and augment the proliferation of activated T cells through the cell-intrinsic type I IFN signaling pathway. Marrack et al. first reported in 1999 that IFN-α/β plays an important role in maintaining the vitality of T cells in vitro.156 It was then revealed that type I IFN directly stimulated the clonal expansion and effector differentiation of CD8+ T cells in vitro and in vivo, because IFNAR expression by T cells was necessary for this process.157,158 In addition to type I IFN, Zimmerman et al. demonstrated that IFN-γ also promoted the survival and proliferation of tumor-specific T cells by upregulating the expression of survivin and Ifi202.159